CN109715633B - Dopamine-beta-hydroxylase inhibitors - Google Patents

Dopamine-beta-hydroxylase inhibitors Download PDF

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Publication number
CN109715633B
CN109715633B CN201780056790.7A CN201780056790A CN109715633B CN 109715633 B CN109715633 B CN 109715633B CN 201780056790 A CN201780056790 A CN 201780056790A CN 109715633 B CN109715633 B CN 109715633B
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methyl
hydrogen
compound
formula
difluorophenyl
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CN201780056790.7A
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CN109715633A (en
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P·苏亚雷斯达斯尔瓦
T·罗西
L·E·基斯
A·贝利亚弗
P·N·雷奥帕尔玛
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Bial Portela and Cia SA
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Bial Portela and Cia SA
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Priority claimed from GBGB1616201.8A external-priority patent/GB201616201D0/en
Priority claimed from GBGB1713779.5A external-priority patent/GB201713779D0/en
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Abstract

The present invention relates to: (a) compounds of formula Ia (where R is1、R4、R5、R6N and a are as defined herein) and pharmaceutically acceptable salts or solvates thereof; (b) a pharmaceutical composition comprising the compound, salt or solvate; (c) the use of the compound, salt or solvate in therapy; (d) a therapeutic method of treatment using the compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of said compounds

Description

Dopamine-beta-hydroxylase inhibitors
Technical Field
The present invention relates to: (a) compounds useful as dopamine-beta-hydroxylase inhibitors and pharmaceutically acceptable salts or solvates thereof; (b) a pharmaceutical composition comprising the compound, salt or solvate; (c) the use of the compound, salt or solvate in therapy; (d) a therapeutic method of treatment using the compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of said compounds.
Background
The enzyme dopamine- β -hydroxylase (D β H), also known as dopamine β -monooxygenase, is expressed in both the peripheral and Central Nervous System (CNS). D β H catalyzes the specific hydroxylation of Dopamine (DA) to produce noradrenaline (norpinephrine), also known as Noradrenaline (NA). Thus, D β H inhibitors can inhibit the biosynthesis of NA, thereby limiting its concentration and increasing DA levels.
Generally, interest in developing D β H inhibitors has focused on the following hypotheses: inhibition of this enzyme may provide significant clinical improvement in patients with cardiovascular disorders (e.g. hypertension or chronic heart failure). The principle of using D β H inhibitors is based on their ability to inhibit the biosynthesis of NA, which is achieved by enzymatic hydroxylation of DA. Reduction of NA biosynthesis by inhibition of D.beta.H can directly inhibit sympathetic nerve function, the activation of which is a major clinical manifestation of congestive heart failure (Parmley, W.W., Clin. Cardiol., 18: 440-445, 1995). Thus, peripheral D β H inhibitors reduce sympathetic drive. Congestive heart failure patients have elevated concentrations of plasma norepinephrine (Levine, T.B. et al, am.J. Cardiol., 49: 1659-. Chronic and excessive exposure of the myocardium to noradrenaline can lead to heart β1Down-regulation of adrenoreceptors, thus remodeling the left ventricle, arrhythmia and necrosis, all of which reduce the functional integrity of the heart. Congestive heart failure patients with high plasma concentrations of noradrenaline also have the most adverse long-term prognosis (Cohn, J.N. et al, N.Engl.J.Med.,311:819-823, 1984). More importantly, it was observed that plasma noradrenaline concentrations have been elevated in asymptomatic patients without overt heart failure and that subsequent mortality and morbidity could be predicted (Benedict, C.R. et al, Circulation,94:690-697, 1996). Thus, activated sympathetic drive is not only a clinical marker of congestive heart failure, but may also contribute to progressive worsening of the disease.
Inhibitors of D β H have also been found to be useful in CNS disorders including drug addiction, psychiatric disorders, cognitive decline or dementia. For example, cocaine acts primarily by inhibiting presynaptic Dopamine (DA) transporters as well as serotonin and norepinephrine transporters. Synaptic DA levels increase following cocaine administration, and thus DA receptor binding is a key mechanism for cocaine potentiation. Cocaine also modulates opioid systems, particularly the μ -opioid receptor (MOR), the κ -opioid receptor (KOR), and the prodynorphin. Although stimulation of the dopamine pathway may be sufficient to elicit a potentiation of cocaine, DA transporter gene deletion studies have shown that this pathway is not essential for the development of cocaine self-administration. However, selective gene disruption of MOR would prevent the development of cocaine self-administration.
Disulfiram (antitabase) inhibits aldehyde dehydrogenase (ALDH) and has been used for more than 50 years in the treatment of alcoholism (Fuller, R.K. et al, J.Amer.Med.Assoc., 256: 1449-. Surprisingly, further studies have shown that disulfiram is at least as effective as, and possibly even more effective than, treating cocaine addicts who do not consume alcohol (Carroll, K.M. et al, Arch. Gen. Psychiatry, 61: 264-. Thus, the ALDH-independent mechanism must be responsible for the ability of disulfiram to promote cocaine ganglion (Gaval-Cruz, M. et al, mol. Interv., 9: 175-. Subsequently, Schroeder et al tested the effect of disulfiram on cocaine and food self-administration behavior in rats, as well as seeking drug-induced recovery of cocaine (Schroeder, J.P. et al, Neuropsychopharmacology, 35: 2440-. The results indicate that the efficacy of disulfiram in treating cocaine addiction correlates with the inhibition of D β H and the ability to interfere with environmental stimuli to trigger relapse (Schroeder, j.p. et al, Neuropsychopharmacology, 35: 2440-9, 2010).
In addition, the noradrenergic system plays a role in many cognitive domains, including working memory, attention, and memory consolidation (Coull, J.T. et al, NeuroImage, 10: 705-. However, excessive noradrenergic system activity may impair cognition. Animal studies have shown a correlation between excess noradrenergic activity and impairment of attention and working memory (Arnsten, a.f., nat. rev. neurosci., 10: 410- > 22, 2009; Sara, s.j., Neuroscience, 10: 211- > 23, 2009). Other studies have shown a decrease in cognitive performance in humans under stress conditions, indicating that excess noradrenergic activity also affects human cognition (Campbell, H.L. et al, Pharmacol. biochem. Behav., 88: 222-. In view of this correlation between cognitive performance and the activity of the noradrenergic system, a problem remains whether the basal level of activity difference is related to the cognitive performance difference, and whether this relationship is also affected by age. In the peripheral and CNS, noradrenergic system activity is higher in older adults than in younger adults (Featherstone, J.A. et al, J.Gerontol.,42,271-6, 1987; Lawler, B.A. et al, biol.Psychiatry, 38: 185-8, 1995; Supiano, M.A. et al, am.J.Physiol., 259: E422-31,1990). It has been previously demonstrated that cerebrospinal fluid NA concentrations are higher in the elderly than in younger adults, but it is not clear that age differences in the noradrenergic system may be a factor in cognitive differences. Many studies link excess noradrenergic activity with cognitive impairment. Thus, D β H inhibitors have been found to be useful in enhancing cognition, particularly in patients with dementia, including frontotemporal dementia (FTD), parkinson's disease and Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
To date, several inhibitors of D β H have been reported in the literature. Early first and second generation examples were found (e.g. disulfiram (Goldstein, m. et al, Life sci.,3:763,1964) and diethyldithiocarbamate (Lippmann, w. et al, biochem. pharmacol., 18: 2507,1969) or fusaric acid (Hidaka, h.nature,231,1971) and aromatic or alkyl thioureas (Johnson, g.a. et al, j.pharmacol. exp. ther., 171: 80)1970)), has low efficacy, exhibits poor selectivity for D β H, and causes toxic side effects. However, third-generation D β H inhibitors were found to have greater efficacy, such as nepicastat (nepicastat) (RS-25560-509nM) (Stanley, w.c., et al, br.j.pharmacol, 121: 1803-1809,1997) which were developed for early clinical trials. Although it was originally developed for peripheral indications (hypertension and congestive heart failure), an important finding was the finding that nepicastat crosses the Blood Brain Barrier (BBB), being able to cause central as well as peripheral effects.
Nepicastat and its analogs are disclosed in WO 95/29165. Furthermore, WO 2004/033447 and WO 2008/136695 disclose D β H inhibitors with high efficacy and significantly reduced brain pathways, resulting in potent peripherally selective D β H inhibitors. However, these compounds exhibit no effect in the CNS or primarily peripheral effects, potentially leading to unwanted secondary effects in the cardiovascular system or systemic tissues, such as reduced sympathetic drive. An overview of the mechanisms, substrates and inhibitors of D β H is given by Beliaev, A. et al in Current Enzyme Inhibition,5,27-43,2009.
Thus, there remains an unmet clinical need for potent, non-toxic peripherally selective inhibitors of D β H that are useful in the treatment of certain cardiovascular disorders, such as hypertension, chronic heart failure, and Pulmonary Arterial Hypertension (PAH). A D β H inhibitor with similar or even higher efficacy than nepicastat but without CNS effects (i.e. not able to efficiently cross the BBB), but showing a long residence time in the periphery to provide long-term D β H inhibition would provide a significant improvement over all D β H inhibitor compounds described so far in the prior art. In addition, these compounds will preferably be orally bioavailable, highly soluble and easier and cheaper to synthesize.
There is an unmet clinical need for potent, non-toxic and CNS-penetrating agent/activity inhibitors of D β H with suitable pharmacokinetic properties that are useful in the treatment of certain CNS disorders, including cocaine addiction, alcohol addiction, opiate addiction adjuvant, FTD cognitive decline, MCI cognitive decline, AD cognitive decline, attention deficit-hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and unipolar depression. A D β H inhibitor with similar or even higher efficacy as nepicastat and with beneficial CNS effects-including the ability to cross the BBB and exhibit long residence times in the brain to provide long-term D β H inhibition in the CNS would provide a significant improvement over all D β H inhibitor compounds described so far in the prior art. In addition, these compounds will preferably be orally bioavailable and easier and cheaper to synthesize.
Summary of The Invention
The present invention provides a compound of formula Ia or a pharmaceutically acceptable salt or solvate thereof:
Figure GDA0003305276230000051
wherein:
R1is hydrogen, C1-C6Alkyl, partially or fully deuterated C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Cyanoalkyl, C1-C6Mercaptoalkyl or amino;
R4is hydrogen or C1-C3An alkyl group;
R5is hydrogen or C1-C2An alkyl group;
or R4And R5Combine together with the carbon atom to which they are attached to form a cyclopropyl ring, wherein CH2Moiety is optionally substituted with two deuterium (D) atoms;
R6is C1-C6Alkyl or partially or fully deuterated C1-C6An alkyl group;
a is C5-C7Cycloalkyl, furyl, thienyl, methylthionyl or
Figure GDA0003305276230000061
Wherein:
X1is hydrogen, halo or methyl;
X1' is hydrogen or halo;
X2is hydrogen, halo or methyl;
X2' is hydrogen or halo;
X3is hydrogen or fluorine;
n is 0 or 1, and when n is 0, the single bond is CH when n is 12Part of the carbon atoms to which they are to be attached.
The invention also relates to a compound of formula Ia as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
The present invention also relates to a compound of formula Ia as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a condition ameliorated by the inhibition of D β H within the CNS.
The invention also relates to a compound of formula Ia as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of a medicament for the treatment of a condition ameliorated by the inhibition of D β H within the CNS.
The present invention also relates to a method of treating or preventing a condition ameliorated by the inhibition of D β H within the CNS, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula Ia as defined above or a pharmaceutically acceptable salt or solvate thereof.
The present invention also relates to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia as defined above or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.
Detailed description of the embodiments
A. Definition of
“C1-C6Alkyl "means a monovalent unsubstituted saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. "C1-C2Alkyl group "," C1-C3Alkyl group "," C1-C4Alkyl "and" C1-C5Alkyl "has a similar meaning.
"partially or fully deuterated C1-C6Alkyl "means C1-C6Alkyl in which some or all of the hydrogen atoms are each selectively replaced by deuterium.
“C3-C6Cycloalkyl "means a monovalent unsubstituted saturated cyclic hydrocarbon group having 3 to 6 carbon atoms. "C5-C7Cycloalkyl "has similar meaning.
“C2-C6Cyanoalkyl "means a monovalent cyano-substituted saturated straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, including those forming a cyano group.
“C1-C6Mercaptoalkyl "means a monovalent thiol-substituted saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms.
"halo" means a fluoro (which may be depicted as-F), chloro (which may be depicted as-Cl), bromo (which may be depicted as-Br), or iodo (which may be depicted as-I) group.
"amino" means-NH2。
"pharmaceutically acceptable Salts" means Salts such as those described in standard text for salt formation, see, for example, P.Stahl et al, Handbook of Pharmaceutical Salts: Properties, Selection and Use (VCHA/Wiley-VCH,2002), or S.M. Berge et al, "Pharmaceutical Salts" (1977) Journal of Pharmaceutical Sciences, 66, 1-19.
By "pharmaceutically acceptable solvate" is meant a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., water or ethanol). Where the solvent is water, the term "hydrate" may be employed. Pharmaceutically acceptable solvates include hydrates and other solvates in which the solvent of crystallization may be isotopically substituted, e.g. D2O、 d6-acetone, d6-DMSO。
"pharmaceutically acceptable excipient" means any ingredient of a pharmaceutical composition or other known pharmacologically active ingredient other than a compound of the present invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
"Therapy" ("Therapy"), treatment "(" treatment "and" treating ") includes both prophylactic and curative treatment of a condition, disease or disorder. It also includes slowing, interrupting, controlling, or stopping the progression of the condition, disease, or disorder. It also includes preventing, curing, slowing, interrupting, controlling, or stopping the symptoms of the condition, disease, or disorder.
Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the disclosure and the appended claims. In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.
B. Compound (I)
The present invention provides a compound of formula Ia, or a pharmaceutically acceptable salt or solvate thereof, as defined above:
Figure GDA0003305276230000081
B0. core structure
In some embodiments of formula Ia, n is 0 and the single bond joins CH when n is 12Part of the carbon atoms to which they are to be attached to form a structure of formula Ib
Figure GDA0003305276230000091
In some embodiments of formula Ia, R4And R5Combine together with the carbon atom to which they are attached to form a structure of formula Ic having a cyclopropyl ring, where CH2Moiety is optionally substituted with two deuterium atoms:
Figure GDA0003305276230000092
in some embodiments, more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of the substituents R of the compound of formula Ia5And A has the stereochemical configuration of formula Id
Figure GDA0003305276230000093
In some embodiments, more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of the substituents R of the compound of formula Ia5And A has the stereochemical configuration of formula Ie
Figure GDA0003305276230000101
Preferred embodiments of formula Ia include compounds of formula Ih
Figure GDA0003305276230000102
In some particularly preferred embodiments of formula Ih, more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of the substituents R of the compound of formula Ih5And A has the stereochemical configuration of formula Iu
Figure GDA0003305276230000103
In other particularly preferred embodiments of formula Ih, more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% of the substituents R of the compound of formula Ih5And A has the stereochemical configuration of formula Iv
Figure GDA0003305276230000111
Other preferred embodiments of formula Ia include compounds of formula Ik
Figure GDA0003305276230000112
In some particularly preferred embodiments of formula Ik, more than 50%, preferably more than 90%, more preferably more than 95% and even more preferably more than 99% have the stereochemical configuration of formula In.
Figure GDA0003305276230000113
B1. Substituent R1
R1Selected from the group consisting of: hydrogen, C1-C6Alkyl, partially or fully deuterated C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Cyanoalkyl, C1-C6Mercaptoalkyl and amino.
R1Preferably selected from the group consisting of: hydrogen and C1-C6An alkyl group.
In some embodiments, R1Is hydrogen.
In some embodiments, R1Is C1-C6An alkyl group.
In some embodiments, R1Is partially deuterated C1-C6An alkyl group.
In some embodiments, R1Is completely deuterated C1-C6An alkyl group.
In some embodiments, R1Is C3-C6A cycloalkyl group.
In some embodiments, R1Is C2-C6Cyanoalkyl group.
In some embodiments, R1Is C1-C6A mercaptoalkyl group.
In some embodiments, R1Is an amino group.
R1Preferably selected from the group consisting of: hydrogen, methyl, d 3-methyl, propyl, cyclopropyl, cyanomethyl, mercaptoethyl and amino.
R1More preferably selected from the group consisting of: hydrogen and methyl.
In some embodiments, R1Preferably hydrogen.
In some embodiments, R1Preferably methyl.
In some embodiments, R1Preferably d 3-methyl.
In some embodiments, R1Preferably propyl.
In some embodiments, R1Preferably cyclopropyl.
In some embodiments, R1Preferably cyanomethyl.
In some embodiments, R1Preference is given to mercaptoethyl.
In some embodiments, R1Preferably amino.
R1Most preferably hydrogen.
B2. Substituent R4(in the absence of R5When combined)
R4Selected from the group consisting of: hydrogen and C1-C3An alkyl group.
In some embodiments, R4Is hydrogen.
In some embodiments, R4Is C1-C3An alkyl group.
R4Preferably selected from the group consisting of: hydrogen and methyl.
In some embodiments, R4Preferably hydrogen.
In some embodiments, R4Preferably methyl.
R4Most preferably hydrogen.
B3. Substituent R5(in the absence of R4When combined)
R5Selected from the group consisting of: hydrogen and C1-C2An alkyl group.
In some embodiments, R5Is hydrogen.
In some embodiments, R5Is C1-C2An alkyl group.
R5Preferably selected from the group consisting of: hydrogen and methyl.
In some embodiments, R5Preferably hydrogen.
In some embodiments, R5Preferably methyl.
R5Most preferably hydrogen.
B4. Substituent R6
R6Selected from the group consisting of: c1-C6Alkyl and partially or fully deuterated C1-C6An alkyl group.
R6Preferably is C1-C6An alkyl group.
In some embodiments, R6Is partially deuterated C1-C6An alkyl group.
In some embodiments, R6Is completely deuterated C1-C6An alkyl group.
R6Preferably selected from the group consisting of: methyl, n-butyl and d3-methyl.
In some embodiments, R6Preferably methyl.
In some embodiments, R6Preferably n-butyl.
In some embodiments, R6Preferably d 3-methyl.
R6Most preferably methyl.
B5. Substituent A
A is selected from the group consisting of: c5-C7Cycloalkyl, furyl, thienyl, methylthiophenyl and
Figure GDA0003305276230000141
wherein:
X1is hydrogen, halo or methyl;
X1' is hydrogen or halo;
X2is hydrogen, halo or methyl;
X2' is hydrogen or halo; and is
X3Is hydrogen or fluorine.
Preferably, A is
Figure GDA0003305276230000151
Wherein X1、X1’、X2、X2' and X3As defined above.
More preferably, A is
Figure GDA0003305276230000152
Wherein:
X1is hydrogen, fluorine, chlorine or methyl;
X1' is hydrogen, fluorine or chlorine;
X2is hydrogen, fluorine, chlorine, bromine or methyl;
X2' is hydrogen, fluorine, chlorine or bromine; and is
X3Is hydrogen or fluorine.
In a preferred embodiment, X1、X1’、X2、X2' and X3Not all are hydrogen.
Preferably, a is selected from the group consisting of:
Figure GDA0003305276230000161
most preferably, a is selected from the group consisting of:
Figure GDA0003305276230000171
B6. specific embodiments of the Compounds of formula I
Substituent R1、R4、R5、R6、A、X、X1、X1’、X2、X2' and X3Have been discussed in the above-mentioned B1 to B5. The "substituent" embodiments may be combined with any of the "core structure" embodiments discussed above in B0 to form further embodiments of the compound of formula Ia. All embodiments of the compounds of formula Ia formed by combining the "substituent" embodiments and the "core structure" embodiments discussed above are within the scope of applicants' invention, and some preferred other embodiments of the compounds of formula I are provided below.
In some embodiments of formula Ia, the structures of formulae Ih, Ik, and In (specifically formula Ih) are highly preferred
Figure GDA0003305276230000181
Wherein:
R1selected from the group consisting of: hydrogen and methyl;
R4(if present) is selected from the group consisting of: hydrogen and methyl;
R5(if present) is selected from the group consisting of: hydrogen and methyl;
R6is methyl; and is
A is selected from the group consisting of:
Figure GDA0003305276230000182
in some embodiments of formula Ia, the structure of formula Ir is even more highly preferred
Figure GDA0003305276230000191
Wherein:
a is selected from the group consisting of:
Figure GDA0003305276230000192
the following compounds represent specific embodiments of the present invention:
(5aS,6aR) -5a- (2.5-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(5aS,6aR) -5a- (3, 5-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(S) -1-butyl-6- (3, 5-difluorophenyl) -6, 7-dihydro-2H-pyrrolo [1,2-c ] imidazole-3 (5H) -thione;
(S) -6- (3, 5-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(R) -1-methyl-6- (2,3,5, 6-tetrafluorophenyl) -2,5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(S) -1-methyl-6- (2,3,5, 6-tetrafluorophenyl) -2,5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(S) -6- (2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(5aS,6aR) -5a- (5-chloro-2-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(5aS,6aR) -5a- (5-chloro-2-fluorophenyl) -1- (methyl-d3) -5,5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thione;
(R) -6- (3-chloro-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(S) -6- (3-chloro-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(5aS,6aR) -5a- (3-bromo-2, 6-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(5aS,6aR) -5a- (5-bromo-2-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(5aS,6aR) -5a- (3-chloro-2, 6-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(R) -6- (3-bromo-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(S) -6- (3-bromo-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(5aS,6aR) -5a- (3-chloro-5-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione;
(5aS,6aR) -5a- (5-bromo-2-fluorophenyl) -1- (methyl-d3) -5,5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thione;
(S) -6- (5-bromo-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione
(R) -1-methyl-6- (2,3, 6-trifluorophenyl) -6, 7-dihydro-2H-pyrrolo [1,2-c ] imidazole-3 (5H) -thione
(R) -6- (5-bromo-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(R) -6- (2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione;
(R) -6- (5-chloro-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione; and
(S) -6- (5-chloro-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione.
C. Composition comprising a metal oxide and a metal oxide
The compounds of the present invention intended for pharmaceutical use may be administered alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or as any combination thereof). Typically, they will be administered in a formulation in combination with one or more pharmaceutically acceptable excipients. Accordingly, the present invention also relates to a pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia as defined above or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.
Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods of preparation are described, for example, in Remington's Pharmaceutical Sciences, 19 th edition (Mack Publishing Company, 1995).
D. Application method
The invention also relates to a compound of formula Ia as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy, in particular in the treatment of a condition ameliorated by the inhibition of D β H.
The invention also relates to the use of a compound of formula Ia as defined above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a condition ameliorated by the inhibition of D β H.
The present invention also relates to a method of treating a condition ameliorated by the inhibition of dopamine-beta-hydroxylase, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula Ia as defined above or a pharmaceutically acceptable salt or solvate thereof.
Conditions ameliorated by inhibition of D β H outside the CNS can include (but are not limited to): cardiovascular disorders, such as hypertension, chronic heart failure and Pulmonary Arterial Hypertension (PAH).
Conditions ameliorated by inhibition of D β H within the CNS can include (but are not limited to): cocaine addiction, alcohol addiction, addictive opioid addiction, cognitive decline in FTD, cognitive decline in MCI, cognitive decline in AD, ADHD, PTSD, and unipolar depression.
E. General synthetic methods
The methods for synthesizing the compounds of the present invention are illustrated by the following schemes. The starting materials and reagents for preparing these compounds are available from commercial suppliers or may be prepared by methods apparent to those skilled in the art. The option of including deuterium at a specific position is not shown in order to make the protocol easier to read. Specifically, deuterated products can be prepared using specific deuterated starting materials, including but not limited to those used in the examples below.
Compounds of formula Ia can generally be synthesized by the methods outlined in scheme 1:
scheme 1
Figure GDA0003305276230000231
The starting materials in scheme 1 can generally be synthesized by the methods outlined in scheme 2:
scheme 2
Figure GDA0003305276230000232
The starting material of scheme 2 (when n ═ 0) can generally be synthesized in enantiomerically enriched or racemic form by the method outlined in scheme 3:
scheme 3
Figure GDA0003305276230000241
At R4And R5When combined to form a cyclopropyl group, the starting materials in scheme 1 can generally be synthesized by the methods outlined in scheme 4:
scheme 4
Figure GDA0003305276230000242
The starting material of scheme 4 can generally be synthesized by the method outlined in scheme 5:
scheme 5
Figure GDA0003305276230000243
In turn, the starting material of scheme 5 can be synthesized, typically by the methods outlined in scheme 6, as an enriched enantiomer or racemate and including specific deuterations:
scheme 6
Figure GDA0003305276230000251
According to said synthesis, the present invention provides a process for the preparation of a compound of formula Ia
Figure GDA0003305276230000252
The method comprises reacting a compound of formula IIa, wherein n, R4、R5、R6And A is as defined for formula Ia above
Figure GDA0003305276230000253
And formula R1-N ═ C ═ S compound reaction.
Thus, compounds of formula IIa (wherein n, R4、R5、R6And a is as defined for formula Ia above) are useful intermediates that represent other embodiments of the invention.
F. Examples of the embodiments
All compounds and intermediates were characterized by NMR. Spectra were recorded on a Bruker Avance III 600MHz spectrometer using solvent as internal standard.13The C spectrum is recorded at 150MHz and1the H spectrum is recorded at 600 MHz. Data are reported in the following order: approximate chemical shift (ppm), number of protons, multiplicities (br, broad; d, doublet; m, multiplet; s, singlet; t, triplet) and coupling constants (Hz).
Room temperature in the following schemes means a temperature in the range of 20 ℃ to 25 ℃.
Preparation of example 1
Step 1: (E) -1, 3-difluoro-5- (2-nitrovinyl) benzene
Figure GDA0003305276230000261
To a solution of methanol (72mL), water (36mL) and 2.5M sodium hydroxide (32.4mL,81mmol) was added dropwise a solution of 3, 5-difluorobenzaldehyde (10g,70.4mmol) and nitromethane (4.36mL,81mmol) in methanol (12.00mL) at 5 ℃ over 30min while maintaining the internal temperature between 5 ℃ and 10 ℃ under external cooling. The reaction was then stirred for a further 0.5h with cooling and then a solution of concentrated HCl (11.73mL,141 mmol) in water (36mL) was added in one portion with stirring at 0-10 ℃. The resulting crystals were collected, washed with water and dried to give a pale yellow powdery product. (yield: 7.0g, 54%).
Step 2: (R) -2- (1- (3, 5-difluorophenyl) -2-nitroethyl) malonic acid diethyl ester
Figure GDA0003305276230000262
To a stirred solution of (E) -1, 3-difluoro-5- (2-nitrovinyl) benzene (7.4g,40.0 mmol) in anhydrous tetrahydrofuran (75mL) at room temperature under stirring was added 4- ((S) -hydroxy ((1S,2R,4S,5R) -5-vinylquinuclidin-2-yl) methyl) quinolin-6-ol (CAS number 70877-75-7) (0.620g,1.999mmol), followed by diethyl malonate (8.65mL, 56.7 mmol). The mixture was cooled to-5 ℃ to-7 ℃ under an inert atmosphere and stirred for 20h under cooling. The mixture was immediately evaporated to dryness under vacuum and the residue was taken up in dichloromethane (100mL), washed with 1M HCl, brine, over MgSO4Dried and filtered over a pad of silica. The filtrate was concentrated to 20mL and the residue crystallized after dilution with petroleum ether (ca. 50 mL). The mixture was further diluted with petroleum ether (120mL) and aged at 5-10 ℃. The resulting solid was collected, washed with petroleum ether, and dried to yield the product as an off-white powder. (yield: 9).1g,70％)。
And step 3: (4R) -4- (3, 5-difluorophenyl) -2-oxopyrrolidine-3-carboxylic acid ethyl ester
Figure GDA0003305276230000271
To a suspension of diethyl (R) -2- (1- (3, 5-difluorophenyl) -2-nitroethyl) malonate (9g,26.1 mmol) in methanol (150mL) was added nickel (II) chloride hexahydrate (6.20g, 26.1mmol), followed by addition of sodium borohydride (7.89g,209mmol) portion by portion under ice-cooling. The mixture was stirred at rt for 6h, then quenched with ammonium chloride solution (250mL), diluted with dichloromethane (150mL), acidified to pH 2 with 6M HCl, and stirred for 16 h. The mixture was immediately extracted with dichloromethane and the organic phase was passed over MgSO4Dried and evaporated to dryness to yield a beige powder product. (yield: 6.87g, 98%).
And 4, step 4: (4R) -4- (3, 5-difluorophenyl) -2-oxopyrrolidine-3-carboxylic acid
Figure GDA0003305276230000272
To a stirred solution of ethyl (4R) -4- (3, 5-difluorophenyl) -2-oxopyrrolidine-3-carboxylate (6.85g,25.4 mmol) in ethanol (100mL) was added 1M sodium hydroxide (30.5mL, 30.5 mmol). The resulting suspension was stirred for 1h, then the organics were removed in vacuo and the residue was dissolved in water (250 mL). The product was crystallized after acidification with 6M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50 ℃ to yield the product as a beige powder, yield: 5.2g,21, 85%.
And 5: (R) -4- (3, 5-difluorophenyl) pyrrolidin-2-one
Figure GDA0003305276230000281
A solution of (4R) -4- (3, 5-difluorophenyl) -2-oxopyrrolidine-3-carboxylic acid (5.2g,21.56mmol) in toluene (300mL) was stirred at reflux for 3h, after which the mixture was evaporated to dryness and crystallized from petroleum ether to give a beige powder. Yield: 4.06g, 96%.
Step 6: (R) -4- (3, 5-difluorophenyl) -2-oxopyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000282
To a stirred solution of (R) -4- (3, 5-difluorophenyl) pyrrolidin-2-one (4.05g,20.54mmol) in dry dichloromethane (15mL) at room temperature was added di-tert-butyl dicarbonate (6.72 g,30.8mmol), followed by N, N-dimethylpyridin-4-amine (2.509g,20.54mmol) and triethylamine (2.86mL,20.54 mmol). The mixture was then stirred at room temperature for 3h, then concentrated in vacuo. Chromatography (petroleum ether-ethyl acetate; 4:1) gave an oil which was crystallized from petroleum ether (60mL) and the product isolated as a white powder. Yield: 6.24g, 88%.
And 7: (4R) -4- (3, 5-difluorophenyl) -2-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000283
To a stirred solution of (R) -tert-butyl 4- (3, 5-difluorophenyl) -2-oxopyrrolidine-1-carboxylate (2g,6.73mmol) in anhydrous diethyl ether (30mL) was added dropwise 65% RED-Al (bis (2-methoxyethoxy) aluminum (III) sodium hydride) (1.212 mL,4.04mmol) in toluene at 0-5 ℃ under nitrogen and the mixture was stirred for 30min with cooling. The mixture was immediately quenched with sodium bicarbonate solution and stirred for 30 min. The organic phase is passed over MgSO4Dried and evaporated to dryness to give the product as a colorless oil. (yield: 2.07g, 93%).
And 8: (4R) -2-cyano-4- (3, 5-difluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000291
To a stirred solution of (4R) -4- (3, 5-difluorophenyl) -2-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (2g,6.68 mmol) in anhydrous dichloromethane (50mL) was added trimethylsilanecarbonitrile (1.792mL,13.36mmol) followed by boron trifluoride etherate (1.863 mL,14.70mmol) at-70 ℃. The mixture was stirred for 4h with cooling, quenched with sodium bicarbonate solution and then warmed to room temperature with stirring. The organic phase is passed over MgSO4Dried, filtered and evaporated to dryness under vacuum. Chromatography (petroleum ether-ethyl acetate; 9:1) gave the compound as a colorless oil. (yield: 1.36g, 66%).
And step 9: (4R) -1- (tert-Butoxycarbonyl) -4- (3, 5-difluorophenyl) pyrrolidine-2-carboxylic acid
Figure GDA0003305276230000292
To a stirred solution of (4R) -2-cyano-4- (3, 5-difluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.35g, 4.38mmol) in ethanol (15mL) was added 3M sodium hydroxide (7.30mL, 21.89mmol) and the solution was gently refluxed (oil bath at 80 ℃) for 3 h. The ethanol was immediately removed in vacuo and the residue was diluted with water (10mL) and acidified to pH 2 with 2M HCl at 10-15 ℃. The mixture was extracted with dichloromethane (40mL), the insoluble material in both phases was filtered off, after which the organic phase was washed with brine, over MgSO4Dried and evaporated to dryness to yield 0.89g of a yellow oil. (yield: 62%).
Example 1:(5aS,6aR) -5a- (2.5-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000301
A compound was prepared in analogy to example 3 from (5S) -3- (tert-butoxycarbonyl) -5- (2, 5-difluorophenyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid and methyl magnesium iodide and was isolated as a yellow solid.
1H NMR(DMSO-d6):11.66(1H,br s),7.28(2H,m),7.20(1H,m), 4.06(1H,d,J＝12.0Hz),3.78(1H,d,J＝12.0Hz),2.86(1H,dd,J＝8.2,4.3Hz),2.09(1H,m),2.04(3H,s),1.63(1H,dd,J＝8.1,5.4Hz), 1.13(1H,t,J＝4.8Hz)。
13C NMR(DMSO-d6):158.8,158.7,157.2,157.1,155.7,130.3, 128.8,128.8,128.8,128.7,128.6,117.2,117.1,117.0,116.9,116.8,115.9, 115.8,115.7,115.7,114.8,51.5,32.5,22.4,20.3,9.4。
Example 2:(5aS,6aR) -5a- (3, 5-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000311
A compound was prepared in analogy to example 3 from (5S) -3- (tert-butoxycarbonyl) -5- (3, 5-difluorophenyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid and methyl magnesium iodide and was isolated as a yellow solid.
1H NMR(DMSO-d6):1.63(1H,br s),7.10(3H,m),4.17(1H,d,J ＝12.0Hz),4.00(1H,d,J＝12.2Hz),2.97(1H,dd,J＝8.3,4.3Hz), 2.03(3H,s),1.65(1H,dd,J＝8.2,5.1Hz),1.15(1H,m)。
13C NMR(DMSO-d6):163.4,163.3,161.8,161.7,156,145,130.2, 114.5,110,110,109.9,109.9,102.1,50.7,36.1,25.4,22.4,9.4。
Example 3:(S) -1-butyl-6- (3, 5-difluorophenyl) -6, 7-dihydro-2H-pyrrolo [1, 2-c)]Imidazole-3 (5H) -thiones
Step 1: (4S) -4- (3, 5-difluorophenyl) -2- (methoxy (methyl) carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000312
To (4S) -1- (tert-butoxycarbonyl) -4- (3, 5-difluorophenyl) pyrrolidine-2-carboxylic acid (prepared in a similar manner to step 9 of preparation example 1) (0.982g,3mmol) in vacuo at room temperatureTo a solution in water dichloromethane (10mL) was added bis (1H-imidazol-1-yl) methanone (0.584g,3.60mmol) in portions and the mixture was stirred for 30 min. N, O-dimethylhydroxylamine hydrochloride (0.351g,3.60mmol) was immediately added and stirring continued at room temperature for 40 h. The reaction was then washed with water and the organic phase was over MgSO4Dried and concentrated under vacuum. Chromatography (petrol ether-ethyl acetate; 2:1) gives the product as an off-white solid. (yield: 0.92g, 83%).
Step 2: (4S) -4- (3, 5-difluorophenyl) -2-pentanoylpyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000321
To a solution of tert-butyl (4S) -4- (3, 5-difluorophenyl) -2- (methoxy (methyl) carbamoyl) pyrrolidine-1-carboxylate (0.40g,1.08mmol) in anhydrous tetrahydrofuran (2mL) under nitrogen at 0-5 ℃ was added 2M butyl magnesium bromide (1.62mL,3.24 mmol). The mixture was warmed to room temperature and stirred for 3 h. The mixture was immediately poured onto 1M HCl and then extracted with diethyl ether. The organic phase was washed with brine, over MgSO4Dried and evaporated to dryness. Chromatography (petroleum ether-ethyl acetate; 9:1) gave the product as a colorless oil. (yield: 0.2g, 50%).
And step 3: (S) -1-butyl-6- (3, 5-difluorophenyl) -6, 7-dihydro-2H-pyrrolo [1,2-c ] imidazole-3 (5H) -thione
Figure GDA0003305276230000322
A mixture of (4S) -tert-butyl 4- (3, 5-difluorophenyl) -2-pentanoylpyrrolidine-1-carboxylate (0.19g, 0.517mmol) and 4M HCl (2.59mL,10.34mmol) in dioxane was stirred at room temperature overnight. The mixture was then cooled to room temperature and evaporated to dryness. The oily residue thus obtained was dissolved in a mixture of ethanol (2mL) and water (2mL), after which potassium thiocyanate (0.055g,0.569mmol) and 6M HCl (0.043mL,0.259mmol) were added. The mixture was stirred at reflux for 1h, then at room temperature for 30 min. The solid obtained was collected by filtration, washed with a mixture of ethanol water (1:1) and dried under vacuum at 50 ℃ to give the product as a light beige powder. (yield: 0.12g, 75%).
1H NMR(DMSO-d6):11.71(1H,s),7.13(3H,m),4.14(1H,dd,J ＝11.2,7.9Hz),4.07(1H,quin,J＝8.1Hz),3.67(1H,dd,J＝11.1,8.3 Hz),3.20(1H,dd,J＝15.0,7.8Hz),2.84(1H,dd,J＝15.1,8.8Hz), 2.35(2H,t,J＝7.5Hz),1.50(2H,m),1.26(2H,m),0.86(3H,t,J＝7.4 Hz)。
13C NMR(DMSO-d6):163.3,163.2,161.7,161.6,155.1,145.8, 145.7,145.6,127.6,120,110.8,110.7,110.6,110.6,102.6,102.5,102.3, 49.9,46.5,30.4,29.8,23.6,21.5,13.6。
Example 4:(S) -6- (3, 5-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Step 1: ((4S) -2- (cyano (hydroxy) methyl) -4- (3, 5-difluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000331
To a stirred solution of (4S) -4- (3, 5-difluorophenyl) -2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (1.2g, 3.85mmol) in a mixture of tetrahydrofuran (10mL) and water (5mL) was added potassium cyanide (0.301g,4.63mmol) followed by concentrated HCl (0.319mL,3.85 mmol). The mixture was stirred for 8h and then extracted with dichloromethane. The organic phase was washed with brine, over MgSO4Dried and evaporated to dryness to give (4S) -2- (cyano (hydroxy) methyl) -4- (3, 5-difluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. (yield: 1.44g, 99%).
Step 2: (4S) -4- (3, 5-difluorophenyl) -2- (2-ethoxy-1-hydroxy-2-oxoethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000341
Reacting (4S) -2- (cyano (hydroxy) methyl) -4- (3)A mixture of tert-butyl, 5-difluorophenyl) pyrrolidine-1-carboxylate (1.43g,3.80mmol) and 2M HCl (28.5mL,57.1mmol) was stirred at reflux for 16 h. After cooling to room temperature, the mixture was filtered through a plug of celite to remove insoluble coloured precipitates, then the filtrate was evaporated to dryness under vacuum. The residue was azeotroped twice with absolute ethanol and the residue was taken up in absolute ethanol (20 mL). The solution thus obtained was treated with 4M HCl in dioxane (9.51mL,38.0mmol) and stirred at reflux for 2 h. The mixture was evaporated to dryness and then azeotroped with anhydrous ethanol. The resulting semi-solid was taken up in absolute ethanol (30mL), neutralized to pH 6-7 by addition of triethylamine, followed by addition of a second crop of triethylamine (0.530mL,3.80mmol), followed by di-tert-butyl dicarbonate (0.830g,3.80 mmol). The reaction was stirred at room temperature for 2h and then evaporated to dryness at 40 ℃. The residue was partitioned between dichloromethane and water and the organic phase was passed over MgSO4Dried and concentrated under reduced pressure. Chromatography (petroleum ether-ethyl acetate; 9:1, then 4:1) gave the product as a yellow oil. (yield: 1.16g, 79%).
And step 3: (4S) -4- (3, 5-difluorophenyl) -2- (2-ethoxy-2-oxoacetyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000342
To a stirred solution of tert-butyl (4S) -4- (3, 5-difluorophenyl) -2- (2-ethoxy-1-hydroxy-2-oxoethyl) pyrrolidine-1-carboxylate (1.15g,2.98mmol) in anhydrous dichloromethane (25mL) at room temperature was added dess-martin periodinane (3-oxo-1. lambda. triacetate)5-benzo [ d ]][1,2]Iodooxalan-1, 1,1(3H) -triyl ester) (1.266g,2.98mmol) and the mixture was stirred for 2H. The reaction mixture was concentrated in vacuo, after which the residue was purified by chromatography (petroleum ether-ethyl acetate; 4: 1). The product was isolated as a yellow oil. (1.08g, 94% yield).
And 4, step 4: 2- ((4S) -4- (3, 5-difluorophenyl) pyrrolidin-2-yl) -2-glyoxylic acid ethyl ester hydrochloride
Figure GDA0003305276230000351
A stirred solution of (4S) -4- (3, 5-difluorophenyl) -2- (2-ethoxy-2-oxoacetyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.4g,1.043mmol) in 4M HCl in dioxane (5.22mL,20.87 mmol) was stirred at room temperature for 4 h. The reaction mixture was diluted with a mixture of diethyl ether (20mL) and petroleum ether (5mL) and stirred for 30min, and the resulting precipitate was collected immediately, washed with diethyl ether, petroleum ether and dried under vacuum at 50 ℃ to give 2- ((4S) -4- (3, 5-difluorophenyl) pyrrolidin-2-yl) -2-glyoxylic acid ethyl ester hydrochloride as a white powder. (yield: 0.34g, 92%).
And 5: (S) -6- (3, 5-difluorophenyl) -3-thione-3, 5,6, 7-tetrahydro-2H-pyrrolo [1,2-c ] imidazole-1-carboxylic acid ethyl ester
Figure GDA0003305276230000352
A solution of ethyl 2- ((4S) -4- (3, 5-difluorophenyl) pyrrolidin-2-yl) -2-glyoxylate hydrochloride (0.33g,1.032mmol), 6M HCl (0.086mL,0.516mmol) and potassium thiocyanate (0.110g,1.135mmol) in a mixture of ethanol (5mL) and water (5mL) was stirred at reflux for 30 min. The reaction was then cooled to room temperature and the resulting solid was collected, washed with a mixture of ethanol and water (1:1) and dried under vacuum at 50 ℃ to give ethyl (S) -6- (3, 5-difluorophenyl) -3-thione-3, 5,6, 7-tetrahydro-2H-pyrrolo [1,2-c ] imidazole-1-carboxylate as a white solid. (yield: 0.28g, 84%).
Step 6: (S) -6- (3, 5-difluorophenyl) -1-methyl-6, 7-dihydro-2H-pyrrolo [1,2-c ] imidazole-3 (5H) -thione
Figure GDA0003305276230000361
To (S) -6- (3, 5-difluorophenyl) -3-thione-3, 5,6, 7-tetrahydro-2H-pyrrolo [1,2-c ]]To a solution of imidazole-1-carboxylic acid ethyl ester (0.1g,0.308mmol) in anhydrous tetrahydrofuran (2mL) was added sodium borohydride (0.058g,1.542mmol), followed by ice waterBoron trifluoride etherate (0.195mL,1.542mmol) was added with bath cooling. The mixture was warmed to room temperature and stirred for 16 h. The mixture was immediately cooled again to 0-5 ℃ and quenched with 2M HCl (1.233ml,2.467 mmol). The organic solvent was removed in vacuo and the residue was extracted with ethyl acetate. The organic phase is passed over MgSO4Dried, filtered and evaporated to dryness. Chromatography (Petroleum ether-ethyl acetate; 1:1) gave (S) -6- (3, 5-difluorophenyl) -1-methyl-6, 7-dihydro-2H-pyrrolo [1, 2-c) as a white powder]Imidazole-3 (5H) -thione (0.021g,0.079mmol, 25.6% yield).
1H NMR(DMSO-d6):11.69(1H,br s),7.13(3H,m),5.76(1H,s), 4.15(1H,dd,J＝11.2,7.9Hz),4.07(1H,quin,J＝7.8Hz),3.66(1H, dd,J＝11.2,8.4Hz),3.18(1H,m),2.82(1H,ddd,J＝15.0,8.9,1.3Hz), 1.98(3H,s)。
13C NMR(DMSO-d6):163.3,163.2,161.7,161.6,155.1,145.7, 145.7,145.6,127.8,115.4,110.8,110.7,110.6,110.6,102.6,102.5,102.3, 50.0,46.5,30.0,9.4。
Example 5:(R) -1-methyl-6- (2,3,5, 6-tetrafluorophenyl) -2,5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000371
The compound was prepared from (4R) -1- (tert-butoxycarbonyl) -4- (2,3,5, 6-tetrafluorophenyl) pyrrolidine-2-carboxylic acid and methyl magnesium iodide in analogy to example 3 and isolated as off-white powder.
1H NMR(DMSO-d6):11.74(1H,br s),7.85(1H,m),4.49(1H, quin,J＝8.5Hz),4.42(1H,m),4.15(1H,dd,J＝11.6,9.2Hz),3.76(1 H,dd,J＝11.7,7.8Hz),3.27(1H,dd,J＝15.6,9.2Hz),2.89(1H,dd,J ＝15.4,7.9Hz),1.97(3H,s)。
13C NMR(DMSO-d6):155.0,146.4,146.3,146.3,145.3,145.2, 144.8,144.7,144.6,143.7,143.6,127.5,120.5,120.4,120.3,115.3, 105.9,105.7,105.6,48.4,35.9,28.6,9.3。
Example 6:(S) -1-methyl-6- (2,3,5, 6-tetra-methyl)Fluorophenyl) -2,5,6, 7-tetrahydro-3H-pyrrolo [1,2-c]Imidazole-3-thiones
Figure GDA0003305276230000372
The compound was prepared in analogy to example 3 from (4S) -1- (tert-butoxycarbonyl) -4- (2,3,5, 6-tetrafluorophenyl) pyrrolidine-2-carboxylic acid and methyl magnesium iodide and was isolated as a pale beige powder.
1H NMR(DMSO-d6):11.74(1H,br s),7.85(1H,m),4.49(1H, quin,J＝8.5Hz),4.15(1H,dd,J＝11.6,9.2Hz),3.76(1H,dd,J＝11.7, 7.8Hz),3.27(1H,dd,J＝15.6,9.2Hz),2.89(1H,dd,J＝15.4,7.9Hz), 1.97(3H,s)。
13C NMR(DMSO-d6):155,146.4,146.3,146.3,145.3,145.2,144.8, 144.7,144.6,143.7,143.6,127.5,120.5,120.4,120.3,115.3,105.9, 105.7,105.6,48.7,48.4,35.9,28.6,9.3。
Example 7:(S) -6- (2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000381
The compound was prepared from (4S) -1- (tert-butoxycarbonyl) -4- (2, 6-difluorophenyl) pyrrolidine-2-carboxylic acid and methyl magnesium iodide in a similar manner to example 3 and was isolated as a pale beige powder.
1H NMR(DMSO-d6):11.72(1H,br s),7.40(1H,m),7.13(2H,m), 4.41(1H,quin,J＝8.7Hz),4.12(1H,br t,J＝10.1Hz),3.70(1H,dd,J ＝8.8,10.8Hz),3.21(1H,br dd,J＝15.3,9.2Hz),2.84(1H,br dd,J＝ 15.2,8.6Hz),1.97(3H,s)。
13C NMR(DMSO-d6):161.6,161.6,160.0,159.9,155.0,129.8, 129.7,129.7,127.8,116.6,116.5,116.4,115.2,112.3,112.2,112.1,112.1, 48.6,35.4,28.8,9.3。
Example 8:(5aS,6aR) -5a- (5-chloro-2-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000391
The compound was prepared in analogy to example 3 from (1S,5R) -1- (5-chloro-2-fluorophenyl) -4- (methoxy (methyl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester and methyl magnesium iodide. The product was isolated as a beige solid.
1H NMR(DMSO-d6):11.65(1H,br s),7.47(1H,dd,J＝6.5,2.6 Hz),7.42(1H,ddd,J＝8.8,4.4,2.7Hz),7.29(1H,dd,J＝10.0,8.9Hz), 4.06(1H,d,J＝11.7Hz),3.77(1H,d,J＝12.0Hz),2.87(1H,dd,J＝ 8.2,4.3Hz),2.04(3H,m),1.64(1H,dd,J＝8.1,5.4Hz),1.12(1H,t,J ＝4.8Hz)。
13C NMR(DMSO-d6):161.3,159.7,155.7,130.3,130.1,130.1, 129.3,129.3,129.0,128.9,128.3,128.3,117.6,117.4,114.8,51.5,51.5, 32.3,22.3,20.2,9.4。
Example 9:(5aS,6aR) -5a- (5-chloro-2-fluorophenyl) -1- (methyl-d3) -5,5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000401
The compound is prepared in a similar manner to example 3 from (1S,5R) -1- (5-chloro-2-fluorophenyl) -4- (methoxy (methyl) carbamoyl) -3-azabicyclo [3.1.0]]Hexane-3-carboxylic acid tert-butyl ester and methyl-d3-preparation of magnesium iodide. The product was isolated as a light orange solid.
1H NMR(DMSO-d6):11.65(1H,s),7.47(1H,dd,J＝6.6,2.8Hz), 7.42(1H,ddd,J＝8.8,4.4,2.7Hz),7.29(1H,m),4.06(1H,d,J＝11.9 Hz),3.77(1H,d,J＝12.0Hz),2.87(1H,dd,J＝8.3,4.3Hz),1.64(1H, dd,J＝8.3,5.4Hz),1.12(1H,t,J＝4.8Hz)。
13C NMR(DMSO-d6):161.3,159.7,155.7,155.6,130.3,130.1, 130.1,129.3,129.3,129.0,128.9,128.3,128.3,117.6,117.4,114.7,114.6, 51.5,51.5,32.3,22.3,20.2。
Example 10:(R) -6- (3-chloro-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000402
The compound was prepared from (4S) -1- (tert-butoxycarbonyl) -4- (3-chloro-2, 6-difluorophenyl) pyrrolidine-2-carboxylic acid and methyl magnesium iodide in analogy to example 3 and was isolated as an off-white powder.
1H NMR(DMSO-d6):11.73(1H,br s),7.61(1H,td,J＝8.8,5.6 Hz),7.21(1H,t,J＝9.5Hz),4.44(1H,quin,J＝8.6Hz),4.13(1H,dd, J＝11.4,9.2Hz),3.72(1H,dd,J＝11.6,7.9Hz),3.23(1H,m),2.84(1 H,dd,J＝15.5,8.1Hz),1.97(3H,s)。
13C NMR(DMSO-d6):160.2,160.1,158.5,158.5,156.6,156.5,155, 154.9,154.9,129.7,129.7,127.7,118.9,118.7,118.6,116.1,116.1,116.0, 116.0,115.2,113.3,113.3,113.1,113.1,48.5,35.8,28.7,9.4。
Example 11:(S) -6- (3-chloro-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000411
The compound was prepared from (4R) -1- (tert-butoxycarbonyl) -4- (3-chloro-2, 6-difluorophenyl) pyrrolidine-2-carboxylic acid and methyl magnesium iodide in analogy to example 3 and was isolated as a pale beige powder.
1H NMR(DMSO-d6):11.73(1H,br s),7.61(1H,td,J＝8.8,5.6 Hz),7.21(1H,t,J＝9.5Hz),4.44(1H,quin,J＝8.6Hz),4.13(1H,dd, J＝11.4,9.2Hz),3.72(1H,dd,J＝11.6,7.9Hz),3.23(1H,m),2.84(1 H,dd,J＝15.5,8.1Hz),1.97(3H,s)。
13C NMR(DMSO-d6):160.2,160.1,158.5,158.5,156.6,156.5, 154.9,154.9,129.7,129.6,127.7,118.9,118.7,118.6,116.1,116.1,116.0, 115.9,115.2,113.3,113.3,113.1,113.1,48.5,35.7,28.7,9.4。
Example 12:(5aS,6aR) -5a- (3-bromo-2, 6-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000421
A compound was prepared from 2- (3-bromo-2, 6-difluorophenyl) acetonitrile and (R) -2- (chloromethyl) oxirane in analogy to example 3 and isolated as white solid.
1H NMR(DMSO-d6):11.68(1H,br s),7.74(1H,td,J＝8.4,5.9 Hz),7.15(1H,td,J＝9.2,1.2Hz),4.01(1H,d,J＝12.3Hz),3.71(1H, d,J＝12.0Hz),2.72(1H,dd,J＝8.3,4.5Hz),2.05(3H,s),1.65(1H, dd,J＝8.2,5.6Hz),1.25(1H,t,J＝5.0Hz)。
13C NMR(DMSO-d6):161.9,161.9,160.3,160.2,158.8,158.8, 157.2,157.1,155.7,133.0,133.0,130.0,117.2,117.1,115.1,113.5,113.3, 103.7,103.7,103.6,51.4,26.5,21.8,20.9,9.4。
Example 13:(5aS,6aR) -5a- (5-bromo-2-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000422
Step 1: ((1R,2S) -2- (aminomethyl) -2- (5-bromo-2-fluorophenyl) cyclopropyl) methanol
Figure GDA0003305276230000423
To a stirred solution of 2- (5-bromo-2-fluorophenyl) acetonitrile (10g,46.7mmol) in anhydrous tetrahydrofuran (100mL) at room temperature under an inert atmosphere was added (R) -2- (chloromethyl) oxirane (4.38mL,56.1 mmol). The reaction was then cooled to 0 ℃ and2M sodium bis (trimethylsilyl) amide (40.9mL,82mmol) in tetrahydrofuran was added dropwise, maintaining the temperature between 0-5 ℃. The resulting red mixture was immediately allowed to warm to room temperature and stirred for 3 h. The reaction was diluted with anhydrous tetrahydrofuran (100mL), cooled to 0 deg.C and sodium borohydride (7.07g, 187mmol) was added, followed by dropwise addition of boron trifluoride diethyl ether (23.68mL,187 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The resulting pale yellow suspension was then cooled to 0 ℃ and carefully quenched with 2M HCl (140ml,280 mmol). The tetrahydrofuran was evaporated off under vacuum and the aqueous phase was washed with diethyl ether (discarded), then basified to pH 10(3M NaOH) and extracted with dichloromethane. The organic phase is passed over MgSO4Dried, filtered and evaporated to leave a yellow oil. Yield: 11.75g, 73%.
Step 2: ((1S,2R) -1- (5-bromo-2-fluorophenyl) -2- (hydroxymethyl) cyclopropyl) methyl) carbamic acid tert-butyl ester
Figure GDA0003305276230000431
To an ice-cooled solution of ((1R,2S) -2- (aminomethyl) -2- (5-bromo-2-fluorophenyl) cyclopropyl) methanol (11.75g, 42.9mmol) in ethanol (145mL) was added di-tert-butyl dicarbonate (9.35g,42.9 mmol). The solution was stirred at room temperature for 4 h. The solvent was then evaporated and the residue was separated on a column. The title compound was isolated as a yellow foam. Yield: 10.1g, 56%.
And step 3: (1S,5R) -1- (5-bromo-2-fluorophenyl) -4-hydroxy-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Figure GDA0003305276230000432
To a stirred solution of oxalyl chloride (2.60mL,29.7mmol) in anhydrous dichloromethane (62.8mL) was added a solution of DMSO (4.21mL,59.4mmol) in anhydrous dichloromethane (12.5mL) dropwise over 30min at-78 ℃. The reaction mixture was stirred for 5min with cooling, then (((1S,2R) -1- (5-bromo-2-fluorophenyl) -2- (hydroxymethyl) cyclopropyl) was added dropwise over 30min) Methyl) carbamic acid tert-butyl ester (10.1g,27.0mmol) in dry dichloromethane (25 mL). The mixture was stirred at-78 ℃ for 1h, then triethylamine (18.8mL,135 mmol) was added. The reaction was gradually warmed to room temperature and stirred for 2 h. The mixture was immediately washed three times with water over MgSO4Dried, filtered and evaporated to give a yellow oil. Yield: 10.1g, 85%.
And 4, step 4: (1S,5R) -1- (5-bromo-2-fluorophenyl) -4-cyano-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Figure GDA0003305276230000441
To (1S,5R) -1- (5-bromo-2-fluorophenyl) -4-hydroxy-3-azabicyclo [3.1.0] at room temperature under an inert atmosphere]To a stirred solution of hexane-3-carboxylic acid tert-butyl ester (10.1g,27.1mmol) in anhydrous dichloromethane (133mL) was added trimethylsilanecarbonitrile (9.71mL,72.4 mmol). Then, the solution was cooled to-78 ℃ and boron trifluoride diethyl ether (10.08mL, 80.0mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 4h, then NaHCO was added3And the mixture was warmed to room temperature. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were passed over MgSO4Dried, filtered and evaporated to give 10.3g of a yellow oil. Yield: 85 percent.
And 5: (1R,5S) -5- (5-bromo-2-fluorophenyl) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid
Figure GDA0003305276230000442
To a stirred solution of tert-butyl (1S,5R) -1- (5-bromo-2-fluorophenyl) -4-cyano-3-azabicyclo [3.1.0] hexane-3-carboxylate (10.3g,27.0mmol) in ethanol (93mL) at room temperature was added a 3M NaOH solution (45mL,135 mmol). The solution was heated at 80 ℃ for 3 h. The reaction was then cooled to room temperature, ethanol was evaporated and the aqueous phase was acidified with 2N HCl solution, the resulting solid was filtered off and dissolved in a dichloromethane-isopropanol (7:3) mixture. The organic phase was dried over MgSO4, filtered and evaporated to give the title compound as a yellow semi-solid. Yield: 10.5g, 78%.
Step 6: (1S,5R) -1- (5-bromo-2-fluorophenyl) -4- (methoxy (methyl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Figure GDA0003305276230000451
To a stirred solution of ((1R,5S) -5- (5-bromo-2-fluorophenyl) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (2.5g,6.25mmol) in anhydrous dichloromethane (36mL) was added bis (1H-imidazol-1-yl) methanone (1.215g,7.50mmol) portionwise under nitrogen and the reaction stirred for 30min N, O-dimethylhydroxylamine hydrochloride (0.731g,7.50mmol) was added at once and the mixture stirred overnight, then the reaction mixture was diluted with dichloromethane (ca. 60mL) and washed with water the organic phase was dried over MgSO4, filtered and evaporated to give the title compound as a yellow oil, yield: 1.57g, 45%.
And 7: (1S,5R) -4-acetyl-1- (5-bromo-2-fluorophenyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Figure GDA0003305276230000452
To (1S,5R) -1- (5-bromo-2-fluorophenyl) -4- (methoxy (methyl) carbamoyl) -3-azabicyclo [3.1.0] at 0 deg.C]To a stirred solution of hexane-3-carboxylic acid tert-butyl ester (1.57g,3.54mmol) in anhydrous tetrahydrofuran (15mL) was added dropwise magnesium methyliodide (3.54mL,10.62 mmol). The reaction mixture was stirred for 1h with cooling and then quenched by addition of 1M HCl (14.17 ml,14.17 mmol). The mixture was extracted with an ethyl acetate-petroleum ether (1:1) mixture. The organic phase was washed with brine, over MgSO4Dried, filtered and evaporated to give 1.34g of a yellow oil. Yield: 86 percent.
And 8: 1- ((1R,5S) -5- (5-bromo-2-fluorophenyl) -3-azabicyclo [3.1.0] hex-2-yl) eth-1-one hydrochloride
Figure GDA0003305276230000461
To a stirred solution of (1S,5R) -4-acetyl-1- (5-bromo-2-fluorophenyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (1.33g,3.34mmol) was added 4M HCl in dioxane (6.68mL,26.7mmol), and the mixture was stirred at room temperature for 2 h. Diethyl ether was immediately added and the mixture was evaporated to dryness to yield an orange oil. Yield: 1.2g, 91%.
And step 9: (5aS,6aR) -5a- (5-bromo-2-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4] pyrrolo [1,2-c ] imidazole-3 (2H) -thione
Figure GDA0003305276230000462
To 1- ((1R,5S) -5- (5-bromo-2-fluorophenyl) -3-azabicyclo [3.1.0]To a stirred solution of hex-2-yl) ethanone hydrochloride (1.1g,3.29mmol) in a mixture of ethanol (13.5mL) and water (13.5mL) was added potassium thiocyanate (0.351g,3.62mmol), followed by concentrated HCl (0.135mL, 1.644 mmol). The solution was heated at reflux for 1 h. The reaction was cooled to room temperature and then the ethanol was removed. The aqueous phase is extracted with dichloromethane and the organic phase is passed over MgSO4Dried, filtered and evaporated. Chromatography in a dichloromethane-methanol mixture gave the title compound as a beige foam. Yield: 0.9g, 77%.
1H NMR(DMSO-d6):11.65(1H,s),7.59(1H,dd,J＝6.7,2.5Hz), 7.55(1H,ddd,J＝8.7,4.5,2.6Hz),7.24(1H,dd,J＝10.1,8.7Hz),4.05(1 H,d,J＝12.0Hz),3.76(1H,d,J＝12.0Hz),2.87(1H,dd,J＝8.3,4.3Hz), 2.04(3H,s),1.64(1H,dd,J＝8.2,5.3Hz),1.12(1H,t,J＝4.8Hz)。
13C NMR(DMSO-d6):161.8,160.2,155.7,132.9,132.9,132.3, 132.2,130.2,129.4,129.3,118,117.8,116.2,116.2,114.8,51.5,51.5, 32.2,22.2,20.2,9.3。
Example 14:(5aS,6aR) -5a- (3-chloro-2, 6-difluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000471
A compound was prepared from 2- (3-chloro-2, 6-difluorophenyl) acetonitrile in a similar manner to example 13. The product was isolated as a beige solid.
1H NMR(DMSO-d6):11.68(1H,s),7.63(1H,td,J＝8.6,5.8Hz), 7.21(1H,t,J＝8.6Hz),4.01(1H,d,J＝12.2Hz),3.72(1H,d,J＝12.2Hz), 2.73(1H,dd,J＝8.2,4.4Hz),2.05(3H,s),1.65(1H,dd,J＝8.2,5.6Hz), 1.25(1H,t,J＝5.0Hz)。
13C NMR(DMSO-d6):161.2,161.2,159.6,159.6,157.8,157.8, 156.2,156.1,155.7,130.3,130.2,129.9,117.2,117.1,117,115.7,115.7, 115.6,115.6,115.1,112.9,112.9,112.8,112.8,51.4,26.4,21.7,20.8, 9.4。
Example 15:(R) -6- (3-bromo-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000481
A compound was prepared from 3-bromo-2, 6-difluorobenzaldehyde in a similar manner to example 20 and was isolated as a beige powder.
1H NMR(DMSO-d6):11.73(1H,br s),7.72(1H,ddd,J＝8.9,8.1, 5.8Hz),7.16(1H,m),4.44(1H,quin,J＝8.6Hz),4.13(1H,dd,J＝11.5, 9.2Hz),3.71(1H,dd,J＝11.6,7.9Hz),3.23(1H,dd,J＝15.5,9.3Hz), 2.84(1H,dd,J＝15.4,8.1Hz),1.97(3H,s)。
13C NMR(DMSO-d6):160.8,160.8,159.2,159.1,157.5,157.5, 155.9,155.8,155,132.4,132.4,127.7,118.8,118.7,118.6,115.1,113.8, 113.8,113.6,113.6,104.1,104,103.9,103.9,48.5,35.8,28.7,9.3。
Example 16:(S) -6- (3-bromo-2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000482
A compound was prepared from 3-bromo-2, 6-difluorobenzaldehyde in analogy to example 20 using 4- ((R) -hydroxy ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methyl) quinolin-6-ol as catalyst (CAS number 524-63-0) and isolated as a beige powder.
1H NMR(DMSO-d6):11.72(1H,br s),7.72(1H,ddd,J＝8.9,8.1, 5.8Hz),7.16(1H,m),4.44(1H,t,J＝8.7Hz),4.13(1H,dd,J＝11.5,9.2 Hz),3.71(1H,dd,J＝11.6,7.9Hz),3.23(1H,dd,J＝15.5,9.3Hz),2.84 (1H,dd,J＝15.5,8.1Hz),1.97(3H,s)。
13C NMR(DMSO-d6):160.8,160.8,159.2,159.1,157.5,157.5, 155.9,155.8,155,132.4,132.4,127.7,118.8,118.7,118.6,115.1,113.8, 113.8,113.6,113.6,104.1,104,103.9,103.9,48.5,35.8,28.7,9.3。
Example 17:(5aS,6aR) -5a- (3-chloro-5-fluorophenyl) -1-methyl-5, 5a,6,6 a-tetrahydrocyclopropane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000491
The compound was prepared in analogy to example 13 from 2- (3-chloro-5-fluorophenyl) acetonitrile. The product was isolated as a beige solid.
1H NMR(DMSO-d6):11.64(1H,s),7.30(1H,dt,J＝8.7,2.1Hz), 7.28(1H,t,J＝1.6Hz),7.23(1H,dt,J＝10.0,1.8Hz),4.19(1H,d, J＝12.2Hz),3.99(1H,d,J＝12.0Hz),3.00(1H,dd,J＝8.3,4.3Hz),2.03 (3H,s),1.64(1H,dd,J＝8.3,5.2Hz),1.14(1H,t,J＝4.8Hz)。
13C NMR(DMSO-d6):163.1,161.4,156,145,144.9,134.1,134.1, 130.2,123,123,114.5,114.3,114.1,112.9,112.8,50.8,36,36,25.2,22.2, 9.3。
Example 18:(5aS,6aR) -5a- (5-bromo-2-fluorophenyl) -1- (methyl-d3) -5,5a,6,6 a-tetrahydrocyclopropaneAlkane [3,4]]Pyrrolo [1,2-c]Imidazole-3 (2H) -thiones
Figure GDA0003305276230000501
The compound was prepared in analogy to example 13 from 2- (5-bromo-2-fluorophenyl) acetonitrile. The product was isolated as a beige solid.
1H NMR(DMSO-d6):11.65(1H,s),7.59(1H,dd,J＝6.7,2.6Hz), 7.55(1H,ddd,J＝8.7,4.5,2.6Hz),7.23(1H,dd,J＝10.1,8.7Hz),4.05(1 H,d,J＝12.0Hz),3.76(1H,d,J＝12.0Hz),2.87(1H,dd,J＝8.2,4.3Hz), 1.64(1H,dd,J＝8.3,5.4Hz),1.12(1H,t,J＝4.8Hz)。
13C NMR(DMSO-d6):161.8,160.2,155.7,132.9,132.9,132.3, 132.2,130.3,129.4,129.3,118,117.8,116.2,116.2,114.7,51.5,51.5, 32.3,22.2,20.2。
Example 19:(S) -6- (5-bromo-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000502
Prepared in analogy to example 20 from 5-bromo-2-fluorobenzaldehyde using 4- ((R) -hydroxy ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methyl) quinolin-6-ol as catalyst (CAS No. 524-63-0) and isolated as an off-white solid.
1H NMR(DMSO-d6):11.70(1H,br s),7.58(1H,dd,J＝6.7,2.5Hz), 7.53(1H,ddd,J＝8.7,4.5,2.5Hz),7.23(1H,dd,J＝10.3,8.8Hz),4.20(1 H,quin,J＝8.1Hz),4.11(1H,dd,J＝10.9,8.1Hz),3.71(1H,dd,J＝11.3, 7.9Hz),3.18(1H,dd,J＝15.2,8.1Hz),2.85(1H,ddd,J＝15.2,8.3,1.2 Hz),1.98(3H,s)。
13C NMR(DMSO-d6):160.3,158.7,155.1,131.8,131.8,131.4, 131.4,130.6,130.5,127.5,118,117.9,116.5,116.4,115.4,49,40.5,29, 9.3。
Example 20:(R) -1-methyl-6- (2,3, 6-trifluorobenzeneYl) -6, 7-dihydro-2H-pyrrolo [1,2-c]Imidazole-3 (5H) -thiones
Figure GDA0003305276230000511
Step 1: (E) -1,2, 4-trifluoro-3- (2-nitrovinyl) benzene
Figure GDA0003305276230000512
To a solution of methanol (90mL) and 1.5M sodium hydroxide (131mL,197 mmol) at 5 ℃ was added dropwise a solution of 2,3, 6-trifluorobenzaldehyde (30g,187mmol) and nitromethane (16mL,299mmol) in methanol (60mL) over 40min while maintaining the internal temperature between 5 ℃ and 10 ℃ under external cooling. The reaction was then stirred for 30min with cooling, and then acetic acid solution (16mL,281mmol) was added in one portion at 0-10 ℃ with stirring. The resulting mixture was extracted with dichloromethane (about 200mL), the organic phase was washed with brine and dried (MgSO)4) And filtered to give a solution of 1- (2,3, 6-trifluorophenyl) -2-nitroethanol in dichloromethane. Immediately, the above solution (about 270mL) was treated with N, N-lutidine-4-amine (2.289g, 18.74mmol), after which acetic anhydride (21.26mL,225mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then washed with water and sodium bicarbonate solution, respectively. The organic phase was dried over MgSO4, filtered and evaporated to dryness. The crude product was crystallized from a mixture of isopropanol and water to yield a light brown solid. Yield: 38.1g, 88%.
Step 2: (R) -2- (2-Nitro-1- (2,3, 6-trifluorophenyl) ethyl) malonic acid diethyl ester
Figure GDA0003305276230000521
To a mixture of (E) -1,2, 4-trifluoro-3- (2-nitrovinyl) benzene (5g,24.62mmol) and 1- (3, 5-bis (trifluoromethyl) phenyl) -3- ((1R,2R) -2- (dimethylamino) cyclohexyl) thiourea (CAS No. 620960-26-1) (0.305g,0.738mmol) in dry toluene (40 m)l) diethyl malonate (4.88mL,32.0mmol) was added to the cold solution and the solution was held at-20 deg.C (in the refrigerator) for 16h, then the reaction was warmed to room temperature, washed with 30mL 1M HCl solution, over MgSO4Dried, filtered through a pad of silica gel and evaporated to dryness to give diethyl (R) -2- (2-nitro-1- (2,3, 6-trifluorophenyl) ethyl) malonate as a yellow oil. Yield: 10.3g, 98%.
And step 3: (4R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-3-carboxylic acid ethyl ester
Figure GDA0003305276230000522
To a suspension of diethyl (R) -2- (2-nitro-1- (2,3, 6-trifluorophenyl) ethyl) malonate (10.3g, 22.68mmol) in methanol (115mL) was added nickel (II) chloride hexahydrate (5.39g,22.68mmol), followed by addition of sodium borohydride (6.86g,181mmol) portionwise over 30min under ice-cooling. The mixture was stirred at room temperature for 5h, then quenched with 2M HCl solution (60mL), after which concentrated ammonia (5mL) was added. The mixture was then diluted with dichloromethane (150mL), acidified to pH 2 with 6M HCl, and stirred for 16h to give a clear solution. The mixture was immediately extracted with dichloromethane and the organic phase was passed over MgSO4Dried, filtered and evaporated to dryness. Crystallization from petroleum ether yielded the title compound as a light beige powder. (yield: 6.19g, 95%).
And 4, step 4: (4R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-3-carboxylic acid
Figure GDA0003305276230000531
To a stirred solution of ethyl (4R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-3-carboxylate (6g,20.89 mmol) in ethanol (90mL) was added 1M sodium hydroxide (25.1mL,25.1 mmol). The resulting suspension was stirred at room temperature for 2h, then the organics were removed in vacuo and the residue was dissolved in water (50 mL). The product was crystallized after acidification with 6M HCl. The resulting crystals were collected, washed with cold water and dried under vacuum at 50 ℃ to yield a beige powdered product. Yield: 4.75g, 88%.
And 5: (R) -4- (2,3, 6-trifluorophenyl) pyrrolidin-2-one
Figure GDA0003305276230000532
A solution of (4R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-3-carboxylic acid (4.64g,17.90 mmol) in toluene (150mL) was stirred at reflux for 3h, the mixture was immediately evaporated to 30mL, after which petroleum ether was added to give the title compound as a beige powder. Yield: 3.45 g, 90%.
Step 6: (R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000541
To a stirred solution of (R) -4- (2,3, 6-trifluorophenyl) pyrrolidin-2-one (3.35g,15.57 mmol)) in dry dichloromethane (14mL) at room temperature was added di-tert-butyl dicarbonate (5.10g,23.35mmol) followed by N, N-dimethylpyridin-4-amine (1.902g,15.57 mmol). The mixture was then stirred at room temperature for 24h, then diluted to 80mL with dichloromethane and washed with 10% citric acid (80 mL). The organic phase was dried (MgSO)4) Filtered through a pad of silica gel and the filtrate was evaporated to dryness. Crystallization from petroleum ether gave (R) -tert-butyl 2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylate as an off-white powder. Yield: 4.15g, 85%.
And 7: (4R) -2-hydroxy-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000542
To a stirred mixture of tert-butyl (R) -2-oxo-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylate (4g,12.69mmol) in anhydrous diethyl ether (39mL) and tetrahydrofuran (13mL) under nitrogen at 5-7 deg.CTo the solution was added 65% RED-Al (sodium hydrogen bis (2-methoxyethoxy) aluminum (III)) (2.67mL,8.88mmol) in toluene dropwise and the mixture was stirred with cooling for 1 h. The mixture was immediately quenched with sodium bicarbonate solution (about 40mL) and stirred for 30 min. The organic phase is passed over MgSO4Dried, filtered and evaporated to dryness to give the product as a yellow oil. (yield: 4.55g, 96%).
And 8: (4R) -2-cyano-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000551
To a stirred solution of (4R) -tert-butyl 2-methoxy-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylate (4.33 g,11.76mmol) in dry dichloromethane (90mL) was added trimethylsilanecarbonitrile (3.15mL,23.52mmol) followed by boron trifluoride diethyl ether (3.28mL,25.9mmol) at-70 ℃. The mixture was stirred for 4h with cooling, quenched with sodium bicarbonate solution and then warmed to room temperature with stirring. The organic phase is passed over MgSO4Dried, filtered and evaporated to dryness under vacuum to give the title compound as a yellow oil. (yield: 4.41g, 98%).
And step 9: (4R) -2-carbamoyl-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Figure GDA0003305276230000552
To a stirred solution of (4R) -tert-butyl 2-cyano-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylate (4.4g, 11.46mmol) in a mixture of acetone (54mL) and water (18mL) was added urea hydrogen peroxide complex (5.39g,57.3mmol), followed by potassium carbonate (0.317g, 2.292mmol), and the reaction was stirred at room temperature for 16 h. The acetone was then partially removed under vacuum until oil separation. The mixture was diluted with water and petroleum ether and aged at 5-7 ℃ for 1h with stirring (crystallisation occurred). The solid was collected, washed with water, petroleum ether and dried to give (4R) -2-carbamoyl-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester. Yield: 3.46g, 88%.
Step 10: (4R) -1- (tert-Butoxycarbonyl) -4- (2,3, 6-trifluorophenyl) pyrrolidine-2-carboxylic acid
Figure GDA0003305276230000561
A stirred suspension of (4R) -2-carbamoyl-4- (2,3, 6-trifluorophenyl) pyrrolidine-1-carboxylic acid tert-butyl ester (3.36g,9.76mmol) in 2M HCl (73mL,146mmol) was refluxed for 3h to yield a clear solution with minimal dark insoluble material. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in water (about 50mL) and the pH adjusted to 7 by the addition of 1M NaOH (19.52mL,19.52 mmol). The solution was then concentrated to about 50mL and methanol (55mL) was added, followed by di-tert-butyl dicarbonate (2.343g,10.73mmol) and the mixture stirred for 45 min. The methanol was then removed in vacuo and the residue was diluted with water (25mL) and washed with petroleum ether. The aqueous phase was acidified to pH 1-2 by addition of 2M HCl and then extracted with DCM (50 ml). The organic phase is passed over MgSO4Dried, filtered and evaporated to dryness to give (4R) -1- (tert-butoxycarbonyl) -4- (2,3, 6-trifluorophenyl) pyrrolidine-2-carboxylic acid as a pale beige powder. Yield: 2.8g, 83%.
Step 11-14: (R) -1-methyl-6- (2,3, 6-trifluorophenyl) -2,5,6, 7-tetrahydro-3H-pyrrolo [1,2-c ] imidazole-3-thione
Figure GDA0003305276230000562
The compound was prepared from (4R) -1- (tert-butoxycarbonyl) -4- (2,3, 6-trifluorophenyl) pyrrolidine-2-carboxylic acid in a similar manner to example 13 (steps 6-9) and isolated as an off-white powder.
1H NMR(DMSO-d6):11.72(1H,br s),7.47(1H,qd,J＝9.4,5.0 Hz),7.17(1H,tdd,J＝9.6,9.6,3.7,1.9Hz),4.43(1H,quin,J＝8.7Hz), 4.14(1H,dd,J＝11.3,9.2Hz),3.73(1H,dd,J＝11.5,8.1Hz),3.24(1H, dd,J＝15.6,9.2Hz),2.86(1H,dd,J＝15.4,8.4Hz),1.97(3H,s)。
13C NMR(DMSO-d6):156.9,156.9,156.9,156.9,155.3,155.3, 155.3,155.3,155,149.1,149,149,148.9,147.5,147.5,147.4,147.4, 147.3,147.3,145.9,145.9,145.8,145.8,127.6,118.9,118.8,118.8,118.7, 116.5,116.4,116.3,116.3,115.2,112,112,111.9,111.9,111.8,111.8, 111.8,111.7,48.4,35.7,28.6,9.3。
Example 21:(R) -6- (5-bromo-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000571
The compound was prepared from 5-bromo-2-fluorobenzaldehyde in a similar manner to example 20 and isolated as an off-white solid.
1H NMR(DMSO-d6):11.70(1H,br s),7.58(1H,dd,J＝6.6,2.5 Hz),7.53(1H,ddd,J＝8.7,4.5,2.5Hz),7.23(1H,dd,J＝10.3,8.7Hz), 4.20(1H,quin,J＝8.1Hz),4.11(1H,dd,J＝10.9,8.2Hz),3.71(1H,dd, J＝11.3,7.9Hz),3.18(1H,dd,J＝15.2,8.1Hz),2.85(1H,ddd,J＝15.2, 8.4,1.1Hz),1.98(3H,s)。
13C NMR(DMSO-d6):160.3,158.7,155.1,131.8,131.8,131.4, 131.4,130.6,130.5,127.6,118,117.9,116.5,116.4,115.4,49,40.5,29, 9.3。
Example 22:(R) -6- (2, 6-difluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000581
A compound was prepared from 2, 6-difluorobenzaldehyde in a similar manner to example 20 and was isolated as an off-white solid.
1H NMR(DMSO-d6):11.72(1H,br s),7.40(1H,tt,J＝8.4,6.6Hz), 7.13(2H,m),4.41(1H,quin,J＝8.8Hz),4.12(1H,m),3.70(1H,dd, J＝11.4,8.4Hz),3.21(1H,dd,J＝15.2,9.2Hz),2.84(1H,dd,J＝15.4,8.7 Hz),1.97(3H,s)。
13C NMR(DMSO-d6):161.6,161.6,160,159.9,155,129.8,129.7, 129.7,127.8,116.6,116.5,116.4,115.2,112.3,112.2,112.1,112.1,48.6, 35.4,28.8,9.3。
Example 23:(S) -6- (5-chloro-2-fluorophenyl) -1-methyl-2, 5,6, 7-tetrahydro-3H-pyrrolo [1, 2-c)]Imidazole-3-thiones
Figure GDA0003305276230000582
The compound was prepared from 5-chloro-2-fluorobenzaldehyde in analogy to example 20 using 4- ((R) -hydroxy ((1S,2S,4S,5R) -5-vinylquinuclidin-2-yl) methyl) quinolin-6-ol as catalyst (CAS No. 524-63-0) and isolated as a beige solid.
1H NMR(DMSO-d6):11.70(1H,br s),7.46(1H,dd,J＝6.5,2.7 Hz),7.40(1H,ddd,J＝8.8,4.4,2.6Hz),7.29(1H,dd,J＝10.1,8.8Hz), 4.20(1H,quin,J＝8.1Hz),4.11(1H,dd,J＝10.8,8.1Hz),3.72(1H,dd, J＝11.3,7.9Hz),3.18(1H,dd,J＝15.1,8.1Hz),2.85(1H,ddd,J＝15.2, 8.3,1.2Hz),1.98(3H,s)。
13C NMR(DMSO-d6):159.8,158.2,155.1,130.2,130.1,128.9, 128.8,128.5,128.5,127.6,117.6,117.4,115.5,49.1,49.1,40.5,29,9.3。
G. Dopamine-beta-hydroxylase inhibition assay
The ability of a compound to inhibit D β H activity can be assessed using the following cellular assay. For the purposes of the present invention, a compound is considered to be a "D β H inhibitor" if it exhibits an activity within ≦ 20% of the "control%" at 10 μm in the cell assay. Preferred compounds of the invention (including most of the specific examples above) exhibit an activity in the cell assay of < 50% > "control%", at 1.0 μm. More preferred compounds of the invention exhibit an activity in the cellular assay of ≦ 20% of the "control%", at 1.0 μm. Particularly preferred compounds of the invention exhibit an activity in the assay at 100nm within ≦ 50% of the "% control".
SK-N-SH cells (ATCC HTB-11) obtained from LGC Standards (Teddington, UK) were supplemented with 25mM Hepes, 100U/mL penicillin G, 0.25. mu.g/mL amphotericin B, 100. mu.g/mL streptomycin and 10%
Figure GDA0003305276230000591
Fetal bovine serum was cultured in eagle's minimal essential medium. Cells were incubated at 37 ℃ in 5% CO2Growth in a humidified atmosphere of-95% air in a T162 cm flask (Corning, NY). Fetal bovine serum was removed from the cells for 4 hours prior to collection.
To prepare a cell homogenate, the medium was removed and the cell monolayer washed with 50mM Tris-HCl (pH 7.4). The cells were then discarded from the flask and resuspended in 50mM Tris (pH 7.4). The cell suspension was briefly homogenized with Silent Crusher M (Heidolph) and the resulting homogenate was aliquoted and stored frozen at-80 ℃.
Total protein was quantitated in cell homogenates using a BioRad protein assay (BioRad) using a standard curve of BSA (50-250. mu.g/mL).
The D.beta.H activity was measured by modifying the method of Nagatsu and Udenfriend (Nagatsu, T. and S. Udenfriend: "Photometric assay of dopamine-hydrolases activity in human blood, Clin. chem.18(9):980-3,1972) which is based on the enzymatic hydroxylation of tyramine to oclamine. The resulting octopamine is subsequently oxidized to p-hydroxybenzaldehyde and measured spectrophotometrically. Briefly, the reaction mixture (total volume 500 μ l) contained: cell homogenate (75. mu.g total protein), sodium acetate pH 5.0(200 mM), NEM (30mM), CuSO4(5. mu.M), aqueous catalase (0.5mg/mL), Youngin-HCl (1mM), sodium fumarate (10mM), ascorbic acid (10mM), inhibitor or excipient, and tyramine (25 mM). After a preincubation at 37 ℃ for 10min, the reaction was initiated by addition of tyramine. The reaction was run at 37 ℃ for 45min and then quenched with 50. mu.l PCA (2M). The sample was centrifuged at 16100g for 3min and the supernatant was subjected to solid phase extraction. Solid phase extraction was performed using SPE cartridge ISOLUTE SCX-3(100mg,1mL) previously equilibrated with MilliQ water or SPE 2mL fixed 96-well plate ISOLUTE SCX-3(100 mg). The column/plate was centrifuged at 150g for 2 min. The eluate was discarded and 1mL of Mil was usedliQ Water washing the matrix, then eluting the octopamine with 2X 0.25mL ammonium hydroxide (4M). Oxibamide was oxidized to p-hydroxybenzaldehyde with 100. mu.l sodium periodate (2%) for 6min and stopped with 100. mu.l sodium metabisulfite (10%). The absorbance was measured at 330nm on a Spectramax microplate reader (Molecular Devices, Sunnyvale, Calif.). All enzymatic reactions were performed in duplicate. The results are reported in the following table as activity at the inhibitor concentration tested (expressed as% of control).
In addition, the ability of a compound to inhibit D β H activity can be assessed in human plasma using the following assay. For the purposes of the present invention, a compound is considered to be a "D β H inhibitor" if it exhibits activity within ≦ 20% of the "control%" at 10 μm in the assay. Preferred compounds of the invention (including most of the specific examples above) exhibit an activity in the cell assay of < 50% > "control%", at 1.0 μm. More preferred compounds of the invention exhibit an activity in the cellular assay of ≦ 20% of the "control%", at 1.0 μm. Particularly preferred compounds of the invention exhibit an activity in the assay at 100nm within ≦ 50% of the "% control".
Dopamine beta hydroxylase activity in human plasma was measured with minor modifications by previously developed methods (Nagatsu, T. and Udenfriend, S. Photometric assay of dopamine-beta-hydroxylase activity in human blood. Clin. chem.18 (9)980-983, 1972). Catalase, N-ethylmaleimide, tyramine, disodium fumarate, eugenol, sodium acetate, ascorbic acid, copper sulfate, and octopamine were obtained from Sigma Chemical co., St. Louis, mo.63178. Human plasma samples were obtained from healthy donors (Instituto pertuugu Ato do Sangue)
Figure GDA0003305276230000611
Centro Sangue
Figure GDA0003305276230000612
Porto, Portugal). From the date of collection, plasma was stored at-80 ℃ until use. Test compounds were initially prepared in 10mM dimethyl sulfoxide and diluted in dimethyl sulfoxide to the desired concentrationAnd (4) degree. The test compound was further diluted in ultrapure water to a concentration of 20 times the final concentration to be tested. The final concentrations of test compounds were 10nM,100nM and 1000 nM. The various reagents used to constitute the incubation buffer were premixed and consisted of the following components: sodium acetate buffer (1M, pH 5.0,18ml), sodium fumarate (0.2M,4.5ml), ascorbic acid (0.2M,4.5ml, freshly prepared), eugenol (20mM, freshly prepared, 4.5ml), N-ethylmaleimide (0.2M,4.5ml), catalase (10000U/ml, 9ml), copper sulfate (20. mu.M, 4.5ml) and 4.5 ultrapure water. The standard incubation mixture (total volume, 950. mu.l) contained: 50 μ L of compound or vehicle (2% dimethyl sulfoxide); 700 μ L incubation buffer; 125 μ l plasma (or saline for blank reaction or standard curve); 75 μ l saline. The reaction mixture was placed in a water bath, shaken at 37 ℃ and pre-incubated for 10 minutes. Tyramine (0.5M) was added and incubated for 45 minutes. The reaction mass is exposed to air. Samples of enzyme preparation (with 125. mu.l plasma) with 2M perchloric acid added at the end of the pre-incubation period were used as blanks. A blank of each test compound was used. For the oclpamide standard curve, 2M perchloric acid was replaced by increasing concentrations of oclpamide prepared in 2M perchloric acid (0.5, 1, 2.5, 5, 7.5, 10, 15, 20 μ g/ml, final concentration). The incubation was stopped by adding 200. mu.l of 2M moles of perchlorate and the mixture was centrifuged at 9000g for 5 min. The supernatant fluid (800. mu.L) was transferred to a column (SPE cartridge ISOLUTE SCX-3,100mg) and centrifuged at 150g for 2 min. The column was washed twice with 0.5ml of ultrapure water by centrifugation at 150g for 2 min. The adsorbed octopamine was eluted twice with 0.3ml 4M ammonium hydroxide by centrifugation at 150g for 2 min. The octopamine in the eluate was then converted to p-hydroxybenzaldehyde by adding 200 μ l sodium periodate (2%) and incubating for 6 min. Excess periodate was even reduced by the addition of 200 μ l sodium metabisulfite (10%). Spectramax plus 384(Molecular Devices) and software were used
Figure GDA0003305276230000613
PRO software 5.3 Spectrophotometer measures absorbance at 330mm in 96 well plates. The absorbance is linear with the concentration of oclpamide from 0.5 μ g/ml to 20 μ g/ml. Dopamine beta hydroxylase Activity assayThe resulting octopamine/ml plasma/hour was determined as nmol and the effect of the compound was expressed as% control.
The results are reported in the following table (in parentheses) as the activity at the inhibitor concentration tested (expressed as% of control).
H. Biological data
In vitro experiments:
Figure GDA0003305276230000621
numbers in parentheses indicate activity in human plasma assay (in% of control).

Claims (14)

1. A compound of formula Ia, or a pharmaceutically acceptable salt thereof,
Figure FDA0003305276220000011
wherein:
R1is hydrogen, C1-C6Alkyl, partially or fully deuterated C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C2-C6Cyanoalkyl, C1-C6Mercaptoalkyl or amino;
R4is hydrogen or C1-C3An alkyl group;
R5is hydrogen or C1-C2An alkyl group;
or R4And R5Combine together with the carbon atom to which they are attached to form a cyclopropyl ring, wherein the CH2Moiety is optionally substituted with two deuterium atoms;
R6is C1-C6Alkyl or partially or fully deuterated C1-C6An alkyl group;
a is C5-C7Cycloalkyl, furyl, thienyl, methylthionyl or
Figure FDA0003305276220000012
Wherein:
X1is hydrogen, halo or methyl;
X1' is hydrogen or halo;
X2is hydrogen, halo or methyl;
X2' is hydrogen or halo;
X3is hydrogen or fluorine;
n is 0 or 1, and when n is 0, the single bond is CH when n is 12Part of the carbon atoms to which they are to be attached.
2. The compound of claim 1, wherein n is 0.
3. The compound of claim 1, wherein R4And R5Combine together with the carbon atom to which they are attached to form a cyclopropyl ring, wherein the CH2Moieties are optionally substituted with two deuterium atoms.
4. A compound according to any one of claims 1 to 3, wherein more than 50% of substituents R5And A has the stereochemical configuration of formula Id
Figure FDA0003305276220000021
5. A compound according to any one of claims 1 to 3, wherein more than 50% of substituents R5And A has the stereochemical configuration of formula Ie
Figure FDA0003305276220000022
6. A compound according to any one of claims 1 to 3, wherein a is
Figure FDA0003305276220000031
Wherein X1、X1’、X2、X2' and X3As defined in claim 1.
7. A compound according to any one of claims 1 to 3, wherein R1Is hydrogen, methyl, d 3-methyl, propyl, cyclopropyl, cyanomethyl, mercaptoethyl or amino.
8. The compound according to any one of claims 1 to 2, wherein R4Is hydrogen or methyl.
9. The compound according to any one of claims 1 to 2, wherein R5Is hydrogen or methyl.
10. A compound according to any one of claims 1 to 3, wherein R6Is methyl, n-butyl or d3-methyl.
11. A compound according to any one of claims 1 to 3, wherein a is
Figure FDA0003305276220000032
Wherein:
X1is hydrogen, fluorine, chlorine or methyl;
X1' is hydrogen, fluorine or chlorine;
X2is hydrogen, fluorine, chlorine, bromine or methyl;
X2' is hydrogen, fluorine, chlorine or bromine;
X3is hydrogen or fluorine.
12. Use of a compound of formula Ia, or a pharmaceutically acceptable salt thereof, as defined in claim 1, in the manufacture of a medicament for the treatment of a condition ameliorated by the inhibition of dopamine- β -hydroxylase.
13. A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of formula Ia as described in claim 1 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.
14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0003305276220000041
Figure FDA0003305276220000051
Figure FDA0003305276220000061
Figure FDA0003305276220000071
Figure FDA0003305276220000081
Figure FDA0003305276220000091
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CA3037692A1 (en) 2018-03-29
US10975083B2 (en) 2021-04-13
TW201817728A (en) 2018-05-16
JOP20190050A1 (en) 2019-03-20
AU2017330175A1 (en) 2019-04-04
AU2017330175B2 (en) 2022-02-17
IL265139B (en) 2021-08-31
WO2018056854A1 (en) 2018-03-29
BR112019004248A2 (en) 2019-06-04
US20220017523A1 (en) 2022-01-20
KR20190080864A (en) 2019-07-08
CL2019000662A1 (en) 2019-07-26
US20200181148A1 (en) 2020-06-11
CA3036650A1 (en) 2018-03-29
JOP20190049A1 (en) 2019-03-20
JP2019529460A (en) 2019-10-17
EP3515917A1 (en) 2019-07-31
CL2019000661A1 (en) 2019-07-26
IL265138B (en) 2021-08-31
CO2019002523A2 (en) 2019-05-31
PE20190964A1 (en) 2019-07-08
US11034695B2 (en) 2021-06-15
WO2018056855A1 (en) 2018-03-29
UA125479C2 (en) 2022-03-30
AU2017330174A1 (en) 2019-04-04
KR20190076967A (en) 2019-07-02
CN109715155A (en) 2019-05-03
US20190337950A1 (en) 2019-11-07

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